Details

Autor(en) / Beteiligte

• Boschelli, Diane H
• Wu, Zhipei
• Klutchko, Sylvester R
• Showalter, H. D. Hollis
• Hamby, James M
• Lu, Gina H
• Major, Terry C
• Dahring, Tawny K
• Batley, Brian
• Panek, Robert L
• Keiser, Joan
• Hartl, Brian G
• Kraker, Alan J
• Klohs, Wayne D
• Roberts, Bill J
• Patmore, Sandra
• Elliott, William L
• Steinkampf, Randy
• Bradford, Laura A
• Hallak, Hussein
• Doherty, Annette M

Titel

Synthesis and Tyrosine Kinase Inhibitory Activity of a Series of 2-Amino-8H-pyrido[2,3-d]pyrimidines:  Identification of Potent, Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitors

Ist Teil von

• Journal of medicinal chemistry, 1998-10, Vol.41 (22), p.4365-4377

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

1998

Quelle

MEDLINE

Beschreibungen/Notizen

• Screening of a compound library led to the identification of 2-amino-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidine (1) as a inhibitor of the platelet-derived growth factor receptor (PDGFr), fibroblast growth factor receptor (FGFr), and c-src tyrosine kinases (TKs). Replacement of the primary amino group at C-2 of 1 with a 4-(N,N-diethylaminoethoxy)phenylamino group yielded 2a, which had greatly increased activity against all three TKs. In the present work, variation of the aromatic group at C-6 and of the alkyl group at N-8 of the pyrido[2,3-d]pyrimidine core provided several analogues that retained potency, including derivatives that were biased toward inhibition of the TK activity of PDGFr. Analogues of 2a with a 3-thiophene or an unsubstituted phenyl group at C-6 were the most potent inhibitors. Compound 54, which had IC50 values of 31, 88, and 31 nM against PDGFr, FGFr, and c-src TK activity, respectively, was active in a variety of PDGF-dependent cellular assays and blocked the in vivo growth of three PDGF-dependent tumor lines.